Epidermolysis Bullosa (EB) is a group of heritable skin diseases, which are characterized by chronic fragility and blistering of the skin and mucous membranes. Depending on the subtype, the spectrum of symptoms of the EB is very broad, ranging from minimal skin fragility to very severe symptoms with general complications. Worldwide about 350,000 patients are affected. In some forms of EB, also nails, hair and teeth may be involved. The main types of EB include EB Simplex (EBS), Junctional EB (JEB), Dystrophic EB (DEB) and Kindler syndrome (KS).
DEB affects about 25% of EB patients, can be either dominantly or recessively inherited, and involves defects in Type VII collagen (COL7A1, omim 120120). COL7A1 encoding the alpha-1 chain of collagen VII. Collagen VII functions as an anchoring fibril of the upper part of the dermis to the lamina densa (part of the basement membrane). Following post-translational modification three identical alpha-1 chains fold together with their collagenous triple helix domain. Subsequently, antiparallel dimers are formed that align to form the anchoring fibrils. Collagen VII is synthesized in the skin by keratinocytes and dermal fibroblasts. DEB disease severity roughly correlates with the amount of type VII collagen expression at the basement membrane zone.
Characteristics of Dominant Dystrophic EB (DDEB) include blistering that may be localized to the hands, feet, elbows and knees or generalized. Common findings include scarring, milia, mucous membrane involvement, and abnormal or absent nails. Recessive Dystrophic EB (RDEB) is typically more generalized and severe than DDEB. In addition to the findings of DDEB, other common manifestations of RDEB include malnutrition, anemia, osteoporosis, esophageal strictures, growth retardation, webbing, or fusion of the fingers and toes causing mitten deformity (pseudosyndactyly), development of muscle contractures, malformation of teeth, microstomia and scarring of the eye. The risk of squamous cell carcinoma is greatly increased in this group as well as death from metastatic squamous cell carcinoma.
Within the gene COL7A1 more than 400 different mutations are known. One of the most prevalent affected exons (18% of patients) is exon 73 with about 40 known mutations, most often missense mutations or mutations leading to premature termination codons (PTCs) and glycine substitutions.
Currently there is no treatment for DEB, only palliative care is performed. Severe forms of RDEB impose a high cost on society's healthcare budget: the average costs of dressings and medication is about €200,000 per patient per year.
WO2013/053819 of Institut National de la Santé et de la Recherche Médicale (INSERM) discloses two antisense oligonucleotides targeting exon 73, causing the entire exon to be skipped from the mRNA. The exon-73-deficient mRNA is translated into a functional polypeptide that, although being shorter than the wt protein, behaves very similar to wild-type collagen Vila. One oligonucleotide disclosed is 25 nucleotides in length, displaying a skipping efficiency of 69%, while the other is 30 nucleotides in length, displaying 93% skipping efficiency.